Presidential Address to The American Association of Immunologists

Philippa Marrack, * Jeremy Bender, Michael Jordan, William Rees,* Jennifer Robertson,* Brian C. Schaefer, and John Kappler* Early in the 20th century, scientists realized that grafts and transplanted tumors that differed from their hosts at the MHC were rapidly rejected. Later work showed that lymphocytes were unstoppably interested in MHC differences, so much so that Jerne, in a visionary article in the first issue of the European Journal of Immunology (1), proposed that lymphocyte receptors were selected evolutionarily to react with MHC proteins. His article continued with the proposal that lymphocytes would mutate their receptors during development in the thymus, such that, once mature, they could no longer react with the MHC of their hosts, but would retain the ability to react with other MHC alleles of their species. Jerne’s ideas have been modified as our understanding of thymocyte development has increased. For example, it is now known that T cells rarely, if ever, mutate their a andb TCR genes (2, 3). Also, it is now recognized that thymocytes are selected in two ways for the reactivity of their TCRs, by positive selection for TCRs that react with self-MHC plus self-peptides with low but appreciable affinity (4–9), and by deletion if their TCRs react too well with self-MHC plus self-peptides (10–12). Despite the modifications to Jerne’s hypothesis, which were forced by these findings, immunologists clung to the idea that MHC proteins and theaandb-chains of TCRs must coevolve to have some affinity for each other. There is quite a lot of evidence for the notion.abTCR T cells do react with appreciable fre quency in the absence of priming with foreign MHC proteins (13– 16). The frequency of allo-MHC-reactive T cells in the unprimed population is much higher than for any other Ag except the superantigens. Such a high alloreactivity could be because of an evolutionarily conserved fit between TCRs and MHC. On the other hand, the germline repertoire of ab TCRs may actually be completely random and the high frequency with which TCRs react with MHC may be because of the fact that allogeneic MHC proteins, with the many host-derived peptides to which they are bound, actually comprise thousands of Ags, not one (17), an idea that is supported by the fact that many alloreactive T cells recognize both the allogeneic MHC protein and the peptide bound to it (18). Alternatively, high frequency reaction with foreign MHC may simply be because of positive selection in the thymus for low reaction with self-MHC (plus peptides) and heteroclitic cross reaction between self and foreign MHC. To deal with the complication that positive selection almost certainly biases the repertoire of ab TCRs toward MHC reaction, several groups have tested the allo-MHC reactivity of TCRs from thymocytes that have not been positively and negatively selected or that have been formed by random combinations of TCR aand b-chains (19, 20). The experiments suggested that the unselected abTCR repertoire had some intrinsic affinity for MHC. However, *Howard Hughes Medical Institute, Department of Immunology, National Jewish Medical and Research Center and University of Colorado Health Sciences Center, and Departments ofPharmacology, Biochemistry and Molecular Genetics, and Medicine, University of Colorado Health Sciences Center, Denver, CO 80206